Arsenical compound.



JACOBS, or nouns vnnnou, AND WADE n. LBROWN, MICHAEL I-IEIDEL- AND LOUISE I EAECEQOE NEW YORK, N. Y., ASSIGNORS TO THE ROCKIL "ion new "some.

To a whom it may concern: 3 Be it Known that we, jl fsn'rnn A. JAcons,

Ph. D, residing at Mount Vernon, ii estcounty, New York, Vi gins BROWN, M. residing at Flushine in the city of New .e orlz, borough of, Queens, Queens county, New York, Mrcimni, Huronnnuuonn, Ph. Bu, residing in the city of New York, borough of Manhattan, county and State of New York, and Louise Pimncn, M. ll, residing,- in the city of New York. borough of ltlunhattan, county and State of New York, all citizens of the United States, have jointly invented. a new and Improved Arsenical Compound, of which the following is a specification.

In our co-pending application, Serial No. 194,459, we have described a class of arsenical compounds of use in thetreatment of try: uiosomel or spirocheetul infections, whici may be described as an aromatic arsenic acid possessingun cc-eminoacylamin side chain NHCHRCONRR, in which R nmy be allryl, aryl or hydrogen and R and may be ulliyl or hydrogen, the'aromatic nucleus being joined to the mamino group in said side chain, and especially pointed out the value of the substance N-phenylglycinamid-p arsenic acid. We have further found. as set forth in this application, that a new class oi ursenicals, important for the treatment of trypanosomiasis or spirochzetul infections, is obtained when R" cult" is made to represent an aryl group such as phenyi, tolyl, etc., or their halogen, ni-

einino, hydroxy, ullroxy (which ma include the 'OCH CUUH, OCHJIUNL, or SCH, JONHCONH, group), carboxy, carboxainid, cnrboxureid, sulfonic acid, sulfon- *unid, ocyle-mino, ureniino and other substitution products. Such substituting groups vere used alone and in combination as polyubstituted uryl compounds. The following "orinuiu iincn conu represents the type here presented, in which specification of Letters Patent.

' plicetion. Likewise,

TELLER INEiTXTUTE F011, MEDICAL RESEARCH, OF NEW YORK, N. 55., A'CORPORA- nnsumonri COMPOUND;

Patented se eei, 1918.

X represents any substituting group-in the ortho, mete, or para position "to the amid group. This group may occur several times or in combination with other groups on the same benzene nucleus. 5 In the nucleuscontaining the arsonic acid (AS0 11 group, the iii-sonic acid group may also be in the? ortho or meta position and may also be ac companied by other substituting groups, as described in the aforesaid co-pending upthe NHCH CONH chain joining the two aromatic nuclei may be changed to a homologue such as NHCHRCONH, in which R maybe alkyl or aryl, as described in our co-pending application, Serial No.194,459.

These substances, as arsonic acids, readily dissolve in equivalent amounts of dilute alkali and carbonates to form neutral and stable 'solutidns, from which they are, as a rulg, precipitated by acetic acid or minerai a -i s.

These substances were prepared by thereaction of the aminophenyl-arsonic acid or its homologues or isomers with a-halogenacyl aromatic amino compounds in aqueous ordilute ethyl or methyl alcoholic or dilute acetone solution. In the case of the simpler amins, heating of the phenylglycin ester arsenic acid with the aminseither alone or in a solvent yielded the desired compound. The following examples will demonstrate the method of preparing these substances. Many of them have not only afforded good therapeutic results but form the basis for the synthesis of other substances with still more valuable therapeutic properties. When used directly for therapeutic purposes "the soluble salts are recommended, and particularly the Einample i-N-(PkehyZ-p-ars0nic acid)- glyciomnilid.

60 grams of phenylglycin methyl ester-pyiflfl arsenic acid are mixed with 120 gm..anilin and 120 gm.methyl alcohol, and the mixture heated in the water bath until solution is complete. The methyl alcohol is allowed to boil off and the residue heated for 6 hours. On cooling, the crystalline mass is dissolved in an excess of dilute sodium hydroxid and then an excess of acetic acid is added. The

phenylglycinanilid-p-arsonic acid separates a colorless microcrystalline substance. This, after filtration, is redissolved in dilute ammonia and rcprecipitated with acetic acid. The product so obtained is pure. It forms minute needles which do not melt below 280 C. For the conversion of the above arsonic acid into its sodium salt it is suspended in a small volume of water and dissolved by adding sodium hydroxid solution until faintly alkaline to litmus. The salt is salted out by the addition of an equal volume of saturated sodium acetate solution as glistening scales. It is filtered off and washed with 20 per cent. sodium acetate solution,

then 85 per cent. alcohol, and air dried.

The salt forms glistening s 'ales containing 4H,O of crystallization and dissolves readily in water. Example Il-N-(PhcnyZ-p-arsomlc acid)- glycine/maid.

43.4 grams of p-aminophenylarsonic acid are dissolved in 200 cc. normal sodium hydroxid solution and treated with 52 grams iodoacetanilid and 200 cc. alcohol. In place of the iodoacetanlhd the equivalent amount of bromo or chloroacetanilid can be substituted. In the case of the chloroacetanilid the addition of sodium iodid greatly facilitates the reaction.

The above mixture is boiled for several hours, during which the phenylglycinanilidp-arsonic acid crystallizes out. This, after filtration, is purified in the usual manner, and is identical with the substance given in Example I. In the above reaction any other suitable basic substance can replace the sodium hydroxid.

Ewamplc lll Sod'iu m salt of N (Phenyl- 4-ars0nic acid) ZycyZ 4 awm'nopkeng l urea. I

43.4 grams of arsanilic acid are dissolved in 200 cc. of normal sodium hydroxid solution. To this 46 grams of p-ch-loroacetylaminophenyl urea, 40 grams of sodium iodid and 200cc. of alcohol are added. The mixture is boiled under a reflux. After one hour the product separates. After cooling the mixture is filtered and the residue washed'with water. The crude acid is dissolved in dilute sodium hydroxid and exactly neutralized with acetic acid. The filtrate is treated with an equal volume of saturated sodium acetate solution. On standing the sodium salt separates as microscopic needles. This is filtered and the residue washed with 20 per cent. sodium acetate and then 85 per cent. alcohol.

For puri- *ficatmn the saltus dissolved m a small l A volume of warm water, and prec1pitated by the addition of an equal volume of alcohol. The salt forms microscopic needles containing 4H O of crystallization, which are readily soluble in water.

In the above examples, instead of salting out the salts -with sodium acetate, other methods usually employed for the preparation of salts may be employed. For instance, the aqueous solutions obtained by dissolving the arsonic acids in equivalent amounts of dilute sodium hydroxid or carbonate, etc, may be concentrated to small bulk or precipitated the like.

The foregoing are a few examples of substances falling within the spirit and scope of our invention. -It will be obvious in anyone skilled in the art that many variations in the exact constitution of the substances described may be made without departing from the spirit and scope of our invention. The sodium salts of the compounds are ob tained in the usual way and are especially recommended for use.

What we claim is:

1. As a new product, a. soluble salt of an aromatic arsonic acid having in its molecule by alcohol, acetone and an a-amino-acylarylamin side chain, the

in which R is alkyl or aryl or hydrogen and Ar is an aromatic radical.

, 3. As a new product, the sodium salt of an aromatic arsonic acid having in its molecule an aamino-acylarylamin side chain, the aromatic nucleus containing the arsenic being joined to the a-aininogroup in said side chain, the acyl radical of said side L chain containing a plurality oi? carbon atoms.

4. As a new product, the sodium salt of an aromatic arsonic acid having in its molecule an or-amino acylarylamin side chain having the general formula- NI-ICHRCONHi-ir in which R is alkyl or aryl or hydrogen and Ar is an aromatic radical.

WALTER A. JACOBS, PH. 1). WADE H, BROWN, M. 1). MICHAEL HEIDELBERGER, PH. I). LOUISE PEARCE, ill. I). 

